Parenteral (ip) formulations of pharmaceutical drugs may be administered to patients via intramuscular (im), intravenous (iv) or subcutaneous methodology. The formulation that is developed for a particular drug is dependent on a variety of issues. For example, it is well-known in the art that a formulation should be water-soluble and stable. If freeze-dried the formulation should be capable of forming a well-formed cake and readily reconstitutable (usually in less than one minute). Finally, the formulation should have an acceptable appearance and be prepared from generally accepted, safe excipients.
Stability is an important consideration when designing a formulation, especially for ip applications. For practical reasons, it must be possible to store the formulation for at least two years. Therefore, it is often desirable to freeze dry the formulation to achieve better shelf-life and storage at room temperature.
The instability and poor water solubility (<0.1 mg/ml) of the echinocandin compounds make them particularly difficult to formulate. Most of the formulations tested to date have a shelf life of less than one year. Generally, a shelf life of two or more years is a required. Consequently, a formulation containing an echinocandin compound may require freeze-drying to achieve the necessary stability.
The poor water solubility of the echinocandin compounds affords a further challenge in formulating an ip formulation containing echinocandin active materials. One method of formulating such compounds is by the addition of a surfactant which enhances the solubility of the drug. However, it is generally well-known in the art that the use of a surfactant above a certain concentration generally limits the ability to freeze dry the formulation. A typical freeze-dried formulation has a surfactant concentration less than 5% by weight. According to a market survey of freeze-dried pharmaceutical formulations containing surfactants, the surfactant concentration is usually less than 5% weight in the freeze dried product. See, Carpenter et al., Pharm. Res., 14 (8), 969-975, 1977 to 1997, Physicians' Desk Reference, 50th edition. Medical Economics. Co. NJ (1996). It is generally believed that a formulation with higher concentrations of surfactant is not likely to form a freeze-dried product with desirable characteristics. Specifically, the presence of the surfactant causes the freeze-dried cake to “collapse” resulting in a residue at the bottom of the vial instead of a well-formed cake. The residue is generally less stable, difficult to reconstitute, and non-reproducible.
Because of the poor water solubility of the echinocandin compounds, generally 2-4% (weight by volume) of a surfactant is required to obtain an acceptable concentration of the echinocandin compound in solution. As discussed above, freeze-drying is hindered at this level of surfactant. Therefore, there is a need for a formulation that improves the solubility of echinocandin compounds in water yet allows freeze drying to obtain optimum stability.